PROJECT SUMMARY/ABSTRACT Today, advances in human stem cell science and genetic engineering techniques are enabling researchers to more extensively and precisely insert human cells (and self-organizing mini-organ structures derived from human stem cells) into any stage of embryonic, fetal, and post-natal development of vertebrate animals. These scientific advances are thrilling. Yet they also reveal conceptual, ethical, and procedural limitations in existing ethics guidance for human-animal chimera research. Two sets of influential guidelines for this research ? one set from the National Academies of Sciences and the other from The International Society of Stem Cell Researchers ? represent important landmarks in U.S. and international initiatives to offer oversight to the emerging science of human-animal chimera research. Our review of this guidance and preliminary exploration with major thought leaders, including many who have now agreed to serve on our proposed Working Group, make clear the need for two things: (1) conceptual clarity and normative analysis related to defining and measuring ?humanization? and its significance to animal welfare, and (2) examination and improvement of the oversight system, including greater clarity about who should be responsible (and accountable) for certain aspects of the research and how best to integrate different sets of concerns into a streamlined, efficient review system. To enhance oversight and offer greater conceptual and operational clarity, the proposed project will carry out (1) review of relevant guidances and policies (2) conceptual and normative analyses of philosophical concerns, moral uncertainties, and value conflicts, and (3) empirical analyses of the views of scientists and members of stem cell and animal research oversight committees so that their lived experiences, goals and challenges will inform the actionable recommendations that will emerge from this research project. We will develop a set of educational materials that includes a casebook of challenging protocols with commentaries on how such protocols can be ideally managed and educational modules that help users unpack some of the complex normative issues. We will also develop a white paper that describes actionable recommendations for enhancing the integration of research institutions? stem cell and animal research oversight committees (ESCROs & IACUCs). The educational materials we plan to develop will be designed to aid ESCRO committee and IACUC members in discharging their oversight responsibilities, and to help the public understand this kind of research, what it is, and what it is not.